GABA A RECEPTOR MODULATORS IN THE DEVELOPING RAT FOREBRA

描述：(改编自申请者的描述)促雄激素合成 类固醇(AAS)是睾酮的合成衍生物，近年来 已经成为青春期前和十几岁儿童的主要滥用药物。 众所周知，AAS会对神经内分泌功能产生有害影响，如 以及增加精神症状，包括焦虑，偏执，敌意， 以及对成年人的攻击性。然而，对其机制却知之甚少。 这些化合物在中枢神经系统中的作用，甚至更少 了解这些化合物如何在发育中的大脑中发挥作用。神经 GABAA受体介导的传递是A细胞的主要分子靶点 广泛的治疗和滥用药物，包括神经类固醇， 苯二氮卓类药物和乙醇。调查人员最近表明，AAS 诱导快速、可逆和区域特异性的GABA能电流调制 在青春期前大鼠的前脑中，因此可以被添加到 作为该通道的变构调节剂的物质。这两个 GABAA受体亚单位基因表达的个体发育及发育变化 受体的药理作用在海马区和 出生后头两周的小脑。相比之下， 缺乏描述受体发育变化的信息。 其他前脑区域或下丘脑的药理作用，以及少数 研究评估了GABAA受体表达的变化与 青春期。特别是，还没有进行任何实验来确定 在进展期对AAS的敏感性显著不同 从青春期到成年期。在此应用程序中，调查人员将使用 分子生物学和电生理学方法来确定是否， 伴随着青春期，GABAA受体发生了显著的变化 亚基的表达以及AAS对GABA能的调节能力 突触电流。此外，调查人员将使用 电生理和行为学方法确定慢性AAS 与成年大鼠相比，青春期暴露大鼠在青春期和青春期暴露后 苯二氮卓类药物或神经类固醇，以及原子吸收光谱分析的调节能力 GABAA受体电流，并引起抗焦虑或镇静作用。 总之，这些研究将证明青春期是否与 AAS在GABAA的急性或慢性行动的重大变化 受体，从而提供重要的新信息来表明 青少年滥用AAS或其他精神药物的风险增加 毒品。

DESCRIPTION: (Adapted from the applicant's Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs.